Normal pregnancy requires widespread and relatively rapid changes in the cardiovascular system. The mother is presented with a new vascular bed (the uteroplacental unit) which requires up to 25% of her cardiac output. Other vascular adaptations associated with normal pregnancy include hypervolemia and decreases in peripheral resistance and vascular reactivity to intravenous infusion of vasopressor agents. The mechanisms underlying these vascular changes are poorly understood. The serious complication of pregnancy, pregnancy-induced hypertension (preeclampsia), is characterized by vascular hyperreactivity, vasoconstriction and a fall in plasma volume. Thus, pregnancy-induced hypertension, in some respects, can be considered a condition in which there is a deficiency in the vascular adaptations of normal pregnancy. This condition may complicate up to 26 percent of all pregnancies, and results in birth defects and in a significant number of maternal and 10,000-25,000 perinatal deaths annually. The long-term research objective is to elucidate the etiology and pathophysiology of pregnancy-induced hypertension. The present research proposal is based on the premise that the understanding of the etiology of pregnancy-induced hypertension and the development of methods of prevention and treatment requires a complete and precise knowledge of the mechanism(s) underlying the cardiovascular adapta- tions of normal pregnancy. The objectives of the proposed research are to characterize and elucidate the mechanism(s) underlying pregnancy-induced functional changes in endothelium, smooth muscle and innervation of isolated uterine arteries. The specific aims of this proposal are to char- acterize the effect of pregnancy on isolated uterine arteries with respect to 1) the release of endothelium-derived relaxing factor; 2) the vasodilatory roles of calcitonin gene-related peptide and vasoactive intestinal polypeptide; 3) constriction/relaxation responses to various vasoactive agents; 4) contribution of intracellular calcium sources in mediating the contractile responses to norepinephrine; and 5) adrenergic and cholinergic innervations. The experimental preparations will be isolated uterine (main ascending and arcuate) arteries from pregnant and nonpregnant patients undergoing hysterectomy and uterine, renal, pulmonary and mesenteric arteries from pregnant and nonpregnant rabbits. The experimental techniques will be 1) continual suffusion or perfusion of isolated blood vessels and measurement of tension or pressure responses; 2) measurements of cyclic nucleotides levels by radioassay techniques; 3) measurements of adrenergic, cholinergic and peptidergic innervations by the use of chemical, histochemical and immunocytochemical techniques; and 4) measurements of calcium by atomic absorption spectrophotometry and fluorescent dye techniques.